Potential Use of Adjuvant Bacteriophage Therapy With Debridement, Antibiotics, and Implant Retention Surgery to Treat Chronic Prosthetic Joint Infections

Doub, James B.; Ng, Vincent Y.; Johnson, Aaron J.; Amoroso, Anthony; Kottilil, Shyamasundaran; Wilson, Eleanor

doi:10.1093/ofid/ofab277

Cited by 16 publications

(24 citation statements)

References 17 publications

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“…Several case reports support the potential effectiveness of bacteriophage therapy in treating recalcitrant PJIs when this therapeutic is used as an adjuvant with surgical interventions [ 1 , 19 ]. Without surgery, there is a paucity of data supporting the effectiveness of bacteriophage therapy for Staphylococcal PJIs [ 1 , 4 ]. Subsequently, when using bacteriophage therapy in Staphylococcal PJIs, surgical removal of the synovial fluid that harbors these plasma protein aggregates may be paramount to have total activity of this adjuvant therapeutic against chronic infections.…”

Section: Discussionmentioning

confidence: 99%

Human Plasma Significantly Reduces Bacteriophage Infectivity Against Staphylococcus aureus Clinical Isolates

Shinde¹,

Stamatos²,

Doub³

2022

Cureus

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Bacteriophage therapy has been regaining interest as a potential therapeutic in treating a wide range of infections. However, there is a paucity of knowledge regarding numerous aspects of bacteriophage therapy, thereby hindering the development of proper treatment protocols and effective clinical trials. In this report, the activities of three bacteriophages are evaluated against clinical bacterial isolates in the presence and absence of human plasma (HP). The bacteriophages used in this experiment were residual therapeutic doses from the United States Food and Drug Administration (FDA) approved compassionate use cases to treat recalcitrant prosthetic joint infections (PJIs). Herein we demonstrate that in the presence of HP, the infectivity of these Staphylococcal bacteriophages was significantly reduced compared to the infectivity in the absence of HP. Inhibition of infectivity ranged from 48% to 81% for two methicillin-resistant Staphylococcus aureus (MRSA) clinical isolates independently infected with the same bacteriophage and 98% for a third MRSA clinical isolate infected with a different bacteriophage. In contrast, bacteriophage infectivity of an Enterococcus faecalis clinical isolate was not affected by the presence of HP. We hypothesize that the inhibition is correlated with plasma proteins binding to Staphylococcal surface proteins masking the receptors associated with bacteriophage attachment, thereby reducing infectivity. This has clinical ramifications for bacteriophage therapy use in treating Staphylococcal bacteremia and periprosthetic joint infections.

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Section: Discussionmentioning

confidence: 99%

Human Plasma Significantly Reduces Bacteriophage Infectivity Against Staphylococcus aureus Clinical Isolates

Shinde¹,

Stamatos²,

Doub³

2022

Cureus

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“…While planktonic bacteria cause the overt symptoms of PJI, other factors contribute to the difficulty in treatment, including biofilm formation, persister cells, and small-colony variants (SCVs) [40][41][42][43] . Persister cells are transient subpopulations of bacteria that survive lethal concentrations of antibiotics but revert to the wild-type phenotype when antibiotic pressures are removed 44 .…”

Section: Discussionmentioning

confidence: 99%

Assessment of Staphylococcal Clinical Isolates from Periprosthetic Joint Infections for Potential Bacteriophage Therapy

DePalma

Nandi

Chaudhry³

et al. 2022

Journal of Bone and Joint Surgery

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Background: Bacteriophage therapy is a potential adjunctive treatment for periprosthetic joint infections (PJIs) given the capabilities of bacteriophages to degrade biofilms, self-replicate, and lyse bacteria. However, many aspects of this therapeutic are ill-defined, and the narrow spectrum of bacteriophage activity along with limited available bacteriophage strains curb potential use for specific bacteria such as Staphylococcus aureus at the present time. Therefore, the aim of this study was to determine the feasibility of using bacteriophages for PJI by (1) categorizing the causative organisms in hip and knee PJI at a tertiary academic center and (2) evaluating in vitro activity of a group of bacteriophages against clinical S. aureus PJI isolates.Methods: Patients with chronic hip or knee PJI after undergoing the first stage of a 2-stage revision protocol from 2017 to 2020 were identified retrospectively by a query of the hospital billing database. The causative pathogens in 129 cases were reviewed and categorized. From this cohort, preserved S. aureus isolates were tested against a library of 15 staphylococcal bacteriophages to evaluate for bacterial growth inhibition over 48 hours.Results: S. aureus was the most common pathogen causing PJI (26% [33] of 129 cases). Of 29 S. aureus samples that were analyzed for bacteriophage activity, 97% showed adequate growth inhibition of the predominant planktonic colonies by at least 1 bacteriophage strain. However, 24% of the 29 samples demonstrated additional smaller, slower-growing S. aureus colonies, none of which had adequate growth inhibition by any of the initial 14 bacteriophages. Of 5 secondary colonies that underwent subsequent testing with another bacteriophage with enhanced biofilm activity, 4 showed adequate growth inhibition.Conclusions: Effective bacteriophage therapeutics are potentially available for S. aureus PJI isolates. The differences in bacteriophage activity against the presumed small-colony variants compared with the planktonic isolates have important clinical implications. This finding suggests that bacteriophage attachment receptors differ between the different bacterial morphologic states, and supports future in vitro testing of bacteriophage therapeutics against both planktonic and stationary states of PJI clinical isolates to ensure activity.Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJS/G934).

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“…Consequently, treatment protocols should be devised based on multidisciplinary approaches, as seen with the treatment of prosthetic joint infections, in which direct application of bacteriophage therapy to infected joints has been advocated to be used with surgical debridement surgery in addition to standard-of-care antibiotics. 1,7 These multidisciplinary approaches will not only allow for the best clinical outcomes but also reduce the chance of gene transfer. For personal use only.…”

Section: Clinical Impacts Of Horizontal Gene Transfer In Vivo Bacterial Infectionsmentioning

confidence: 99%

“…Bacteriophage therapy is a novel therapeutic that is gaining increased interest in the treatment of multidrug-resistant infections and as a potential adjuvant in the treatment of chronic biofilm infections. 1,2 Preclinical research suggests that bacteriophages are virulent against planktonic bacteria and, when combined with antibiotics, can help eradicate biofilms. [3][4][5][6] Several case reports support the preclinical work suggesting that bacteriophage therapy may be effective in treating a wide range of infections, ranging from cystic fibrosis infections to recalcitrant orthopedic infections.…”

Section: Introductionmentioning

confidence: 99%

Risk of Bacteriophage Therapeutics to Transfer Genetic Material and Contain Contaminants Beyond Endotoxins with Clinically Relevant Mitigation Strategies

Doub¹

2021

IDR

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Bacteriophage therapy is a promising adjuvant therapeutic in the treatment of multidrug-resistant infections and chronic biofilm infections. However, there is limited knowledge about how to best utilize these agents in vivo, leading to a wide range of treatment protocols. Moreover, while bacteriophages are similar to antibiotics in their antimicrobial effects, these are active viruses and are very different from conventional antibiotics. One main difference that clinicians should be cognizant about is the potential ability of these therapeutics to horizontally transfer genetic material, and the clinical ramifications of such events. In addition, while bacteriophage therapeutics are readily tested for sterility and endotoxins, clinicians should also be aware of other contaminants, such as exotoxins, pathogenicity islands and prophages, that can contaminate bacteriophage therapeutics, and their clinical ramifications. While the perception may be that these are only theoretical issues, regulatory agencies are starting to recommend their evaluation when using bacteriophage therapy and subsequently these topics are discussed herein, as are ways to test for and mitigate the adverse effects of these issues.

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Potential Use of Adjuvant Bacteriophage Therapy With Debridement, Antibiotics, and Implant Retention Surgery to Treat Chronic Prosthetic Joint Infections

Cited by 16 publications

References 17 publications

Human Plasma Significantly Reduces Bacteriophage Infectivity Against Staphylococcus aureus Clinical Isolates

Human Plasma Significantly Reduces Bacteriophage Infectivity Against Staphylococcus aureus Clinical Isolates

Assessment of Staphylococcal Clinical Isolates from Periprosthetic Joint Infections for Potential Bacteriophage Therapy

Risk of Bacteriophage Therapeutics to Transfer Genetic Material and Contain Contaminants Beyond Endotoxins with Clinically Relevant Mitigation Strategies

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